New Target for Obesity-Related Disorders

Inhibiting a microRNA that is overexpressed in obese mice and human patients with nonalcoholic fatty liver disease (NAFLD) and type II diabetes could provide a new approach to treating metabolic disorders and even potentially cancer, scientists claim. A team at the University of Illinois at Urbana–Champaign has shown that treating obese mice with an antisense inhibitor of miR-34a corrects the obesity-related abnormal expression of metabolic genes involved in bile acid, glucose, and fat metabolism, and led to reduced liver fat levels and the restoration of glycogen levels and insulin sensitivity.

Jongsook Kim Kemper, M.D., and colleagues linked miR-34a directly with FGF19, (FGF15 in mice), a recently discovered intestinal hormone that is secreted after a meal and binds to its heptatic membrane receptor complex FGF19 receptor 4 (FGFR4) and its coreceptor β-Klotho (βKL), which triggers the activation of cellular kinases to mediate postprandial metabolic responses. Their in vitro and in vivo studies showed that miR-34a directly binds to and negatively regulates βKL, and that hepatic overexpression of miR-34a in obese mice leads directly to decreased βKL levels, resulting in altered expression of FGF19’s metabolic target genes. Encouragingly, treating obese mice with an antisense inhibitor of miR-34a restored levels of βKL and SIRT1, a known miR-34a target, and led to partial normalization of parameters such as insulin sensitivity and glycogen levels.

“These results indicate that aberrantly elevated hepatic miR-34a in obesity impairs FGF19 signaling largely by inhibiting expression of βKL, which contributes to resistance to hepatic FGF19 signaling in obesity,” the authors state in their published paper in PNAS. “Our studies provide evidence that abnormally elevated miR-34a in obesity plays a causative role in metabolic dysregulation, at least in part, by targeting the hepatic βKL/FGF19 axis.”

Interestingly, miR-34a is also a well-recognized tumor suppressor, and studies have linked deletion of miR-34a expression with liver and colon cancer. The studies of Dr. Kemper et al., thus provide a possible molecular mechanism by which miR-34a suppresses the development of liver cancer through targeting βKL/FGF19 signaling. “Targeting the βKL/FGF19 signaling may thus be of value in the treatment of cancer as well as metabolic disease,” they write, though with the caveat that such targeting would need to be tightly regulated as excess miR-34a is associated with metabolic disease, but miR-34a deficiency is linked to liver cancer.